Natural passive immunity is short-lived after the birth of the child. Key Terms IgG : immunoglobulin G is an antibody isotype. IgA : immunoglobulin A is an antibody isotype. IgA antibodies are transferred from mother to child in colostrum and milk and confer passive immunity.
Their direct role in the infant for repair and regeneration is being investigated. The existence of these hMSCs could prove to be an easily harvested source of multilineage stem cells for the study of cancer and tissue regeneration. Each of these new findings opens the door to future studies of human milk and its effect on the innate immune system and the developing infant.
The innate immune system is the first line of defense against infection and is activated within minutes, reacting in a nonspecific, preprogrammed, and patterned manner to various infectious or foreign non-self stimuli 1. Important developmental immune deficiencies at birth include incomplete physical and chemical barriers, poor innate effector cell function, limited and delayed secretory immunoglobulin A IgA production, incomplete complement cascade function, and insufficient anti-inflammatory mechanisms of the respiratory and gastrointestinal GI tracts.
Human milk is the everchanging secretions of the human breast, an evolving composition of nutrients and active factors. Just as nutrition and protection of the fetus occurs through the mutable nature of the uterus, placenta, and amniotic fluid, the evolution of human milk from colostrum through transitional milk to mature milk provides nutrition and protection appropriate for the time-affected development of the infant 3.
There is a large body of evidence documenting the benefits of human breast milk for human infants, in diminishing morbidity and mortality and protecting against specific infections during the period of breastfeeding 4 — 6. Additional data demonstrate long-term health benefits for the infant and the mother beyond the period of lactation 7 , 8 and led to the current recommendations for duration of exclusive breastfeeding from the American Academy of Pediatrics 9 and the World Health Organization.
Elucidating the relationship between the innate immune system and human milk, as well as their individual and interactive transition over time, remains challenging. The use of modern molecular approaches such as microbial genomics, metabolomics, proteomics, and glycomics has led to novel discoveries in both composition and function of human milk components. Figure 1. Summary of innate immunity and breast milk with groups including components of the innate immunity, maturation of breast milk over lactation, and breast milk by gestation preterm and term.
The chemical barrier of the intestine is predominately the mucus layers lining the GI tract. These mucus layers minimize antigenic contact between epithelial cells and commensal bacteria as well as potentially pathogenic bacteria. Antimicrobial peptides produced by Paneth cells, released into the mucus layer, bolster this chemical barrier innate effect by neutralizing microbes via various mechanisms.
The multifunctionality of individual human milk factors adds another layer of complexity to the innate protection effected within the intestinal mucus layers.
Human milk oligosaccharides HMOs are the predominant glycans and important nutrients in human milk. They function in direct pathogen binding and as prebiotics facilitating the establishment of a healthy infant microbiome 2.
The human milk glycoproteins HMGPs vary in size, structure, and amount in human milk and can be classified based on their location relative to the cell secreted or attached to the cell membrane and the different mucus layers. The specific molecular mechanism of this binding by glycans and interference with infection by the pathogen requires additional clarification. Unraveling the complex glycoprotein—ligand interactions will require application of newer technologies such as nanosurface plasmon resonance and glycan microarrays Lactoferrin LF , another glycoprotein abundant in colostrum and transitional milk and ubiquitously expressed in most exocrine secretions, is one of the best studied glycoproteins in human milk.
Peptide breakdown products of LF, lactoferricin and lactoferrampin, have specific direct antibacterial and antifungal effects There are numerous other HMGPs that have been described but the extent and specificity of their immune function need to be elucidated. Lactadherin can inactivate viruses and limits inflammation by increasing the effective phagocytosis of apoptotic cells.
The sialic acid component of lactadherin seems to directly interact with rotavirus while the protein backbone of the molecule demonstrates a proangiogenic effect on neovascularization.
The list of bioactive glycoproteins in human milk is still expanding, and their individual multifunctional nature is just being described. The immunity provided by these cellular interactions is partially innate and partially the beginning of adaptive immunity Immaturity of the intestinal barrier function, limitations in production of AMPs, and ineffective response and action of epithelial cells and phagocytes place the infant at risk for infection in the neonatal period 25 , Within fresh human milk, there is a remarkable repertoire of heterogeneous living cells.
Cells originating in the breast include lactocytes secretory cells , myoepithelial cells from the ducts as well as progenitor cells and mammary stem cells, and a small number of squamous epithelial cells from the nipple and skin of the breast. Cells originating from the blood, which are in human milk, include immune cells macrophages, neutrophils, and lymphocytes , hematopoietic progenitor cells, and hematopoietic stem cells 27 , The role of live breast cells in human milk in the infant remains uncertain.
New theories are being formulated to explain the fact that these breast milk epithelial cells are capable of motility and can in primary culture form functioning mammospheres 29 , Hassiotou et al.
There are large numbers of macrophages present in early lactation that decrease with the maturation of the milk 31 , These macrophages appear to function by phagocytizing pathogens without initiating a significant, unregulated inflammatory response. An increase in milk leukocytes, above the number usually present at the specific stage of lactation, occurs with infection in either the mother or the infant and suggests a functional role for milk leukocytes in protecting the infant 21 , 33 , Breast milk from mothers of infants with severe bronchiolitis demonstrated an increased number of live cells.
Those live cells produced a specific cytokine profile response when stimulated with live respiratory syncytial virus, a common cause of bronchiolitis Additional studies measuring changes in the bioactive factors in human milk of mothers with sick infants or who are sick themselves for various specific infections should provide more insight into the essential bioactive factors in human milk for protection against specific infections. Using milk from genetically modified mice, Hassiotou et al.
Beyond that, the hMSCs in human milk may provide a ready source of patient-specific stem cells with a true multilineage potential for the study of such stem cells and variables related to breast cancer, tissue regeneration, and even bioengineering. In the past, human milk was considered sterile, but that is far from the truth. Using culture techniques, the majority of bacteria identified as facultative anaerobes in human milk belong to the Staphylococcus and Streptococcus species and other species in smaller numbers Propionibacterium, Rothia, Enterococcus , and Lactobacillus species 37 , Obligate anaerobic bacteria were later identified, Bifidobacterium and Bacteroides species 39 — Culture-independent techniques sequencing and metagenomics analysis have demonstrated a significantly more complex and diverse group of bacteria in human milk 42 , There is a large degree of interindividual variability in the milk microbiome.
Hunt et al. These two analyses shared just three common bacterial groups: Staphylococcus, Streptococcus , and Propionibacterium 34 , Variability between these two studies and others 43 can be attributed to the use of different primers, types of sequencing, comparison with different microbial reference libraries, possible variation due to geographic regions, and timing of the milk collection as well as technique and sterility of milk collection 43 , 46 , The actual origin of the milk microbiota remains uncertain Human milk directly contributes to the establishment of the intestinal microbiota and facilitates a symbiosis between that microbiota and the infant by providing essential nutrients, in particular milk glycans or HMOs, for microbial metabolism Nanthakumar et al.
This leads to fucosylation of surface markers on GI epithelial cells, which enhances the growth of microbes utilizing fucose as part of their metabolism Microorganisms utilize the available glycosaminoglycans, glycoproteins, glycolipids, and oligosaccharides milk glycans as prebiotics to facilitate growth The intestinal microbiota limits the growth of pathogenic bacteria by competition for nutrients and receptors. Specific microbes facilitate the formation of the intestinal mucus layer and the development of the IEC barrier and submucosal lymphoid structures.
Separately, the HMOs bind to surface molecules of bacteria and viruses preventing binding to the intestinal epithelium and appear to diminish intestinal inflammation via signaling pathways He et al. The ultimate benefit to the infant remains to be studied Chatterton et al. The interaction of both sTLRs and sCD14 with other bioactive factors in human milk upregulates and downregulates the action of various TLR-mediated inflammatory responses 60 , LeBouder et al.
They describe specific responses on epithelial cells, monocytes, dendritic cells, and peripheral blood monocytic cells. The responses were different based on which TLRs were activated. Infant formulas did not exhibit such effects. Immunoglobulins are the most recognized immune protective component in human breast milk.
As preformed Igs from the mother, they constitute a discrete group of proteins capable of pathogen recognition. There is a small amount of immunoglobulin G IgG in colostrum and transitional milk, with IgG becoming a much larger proportion of human milk Igs in mature milk Secretory IgA binds pathogens blocking infection without stimulating a significant inflammatory response.
In a largely innate immune-like action, sIgA simply blocks the pathogens contact with the intestinal epithelial layer and traps the pathogens within the mucin layers. The glycan sugar component galactose, fucose, and mannose of sIgA contributes to sIgA resistance to proteolysis in the intestine and functions through a broad spectrum of binding of pathogenic bacteria when compared with the antigen specific binding of the variable region of the Ig structure.
The broad spectrum binding related to the glycan sugar component of sIgA is more consistent with an innate immune response which would explain the absence of an increase in specific sIgA in the milk of mothers with sick infants Immunoglobulin M causes agglutination of recognized pathogens and complement activation as well as innate immune-like activities. The list of pathogens viruses, bacteria, fungi, and parasites recognized by human milk Igs is extensive Gao et al.
There are various other AMPs, in human milk, active in microbe killing, which can supplement the protection of the immature neonatal intestine 14 , LF and its derivatives demonstrate a wide variety of actions on various targets including iron deprivation, destabilization of microbial membranes, binding microbial receptors, affecting chemokine production, stimulating epithelial cell growth, stimulating T-cell growth and differentiation, and production of reactive oxygen species ROSs.
LF also interacts with other components in human milk such as OPN, ceruloplasmin, and neutrophil peroxidase, although the exact significance and function of these interactions remain uncertain 22 , Xanthine oxidoreductase, another protein found in large amounts in milk and upregulated in mature milk, affects mammary epithelium, generation of milk fat droplet membranes, and adds to the bactericidal effect of human milk by synthesizing ROS 64 , These different AMPs do not simply act in microbial recognition and inactivation; each have different secondary functions within the intestine.
Equally important is the limited inflammatory response generated by these AMPs in the gut. Maintenance of a homeostasis between protective inflammation and modulation of inflammation is essential to protecting the infant against infection at the same time as limiting the tissue damage due to inflammation Oxidative stress through the production of free radicals does have some potentially beneficial effects for the host in terms of antibacterial action, immune defense, and signal transduction.
The oxidative activity within the infant must be maintained in equilibrium with antioxidant capacity of tissues These factors act in an innate manner in the intestine. Specific hormones or growth factors predominantly exert their anti-inflammatory effects on intestinal innate immunity through their action on the proliferation and differentiation of IECs and immune cells lymphocytes and macrophages and modulating the inflammatory cytokine response.
Trefoil factor 3 TFF3 is an effector molecule that is present in the intestine and in large amounts in human breast milk. Generally, this molecule improves healing in the GI tract. Glucagon-like peptide 1 GLP-1 is secreted from the enteroendocrine cell in the distal intestine and plays a role in regulating glucose metabolism and food intake. GLP-1 likely acts through vagal afferent pathway ultimately influencing feeding behavior Recently, the first study to report GLP-1 in human milk showed that it was higher in hindmilk compared to foremilk and was correlated with infant weight gain during the first 6 months of life Alternative forms of neonatal nutrition such as formula and TPN do not contain these anti-inflammatory properties, which may put these infants at a disadvantage by creating a relative deficiency of anti-inflammatory factors and activity.
Any enteral feeding directly stimulates growth of the neonatal gut. Variation in human milk oligosaccharides. The factor that promotes the growth of lactobacilli and bifidobacteria, which in turn inhibit the growth of pathogenic microorganisms by decreasing intestinal pH, was originally described as bifidus factor, but currently one of the substances identified as promoting this growth is N-acetyl-glucosamine.
Influence of two infant formulas and human milk on the development of the fecal flora in newborn infants. Acta Paediatr. Subsequently, various oligosaccharides with similar action have been identified, but it is possible that proteins in the milk also show this prebiotic activity. Do the binding properties of oligosaccharides in milk protect human infants from gastrointestinal bacteria?
J Nutr. There are various antioxidants in human milk that can eliminate free radicals and thus limit the damage caused by oxidative stress.
Determination of gamma- and alpha-tocopherols in human milk by a direct high performance liquid chromatographic method with UV-vis detection and comparison with evaporative light scattering detection.
J Chromatogr A. Fat-soluble and water-soluble vitamin contents of breast milk from Japanese women. J Nutr Sci Vitaminol Tokyo. The amino acid composition of human milk corrected for amino acid digestibility. Br J Nutr. Milk from mothers of both premature and full-term infants provides better antioxidant protection than does infant formula. In vitro studies have demonstrated that breast milk degrades naturally-occurring hydrogen peroxide, as well as that produced by neutrophils, possibly due to their catalase content.
Inhibition of neutrophil function by human milk. Cell Immunol. As they contain viable leukocytes, colostrum and breast milk differ from most other secretions. Apart from epithelial cells, macrophages Milk composition of low birth weight infant mothers. More recent studies suggest that the number of macrophages in breast milk has been overestimated, as only a small proportion of these cells contains the characteristic surface markers of macrophages, such as CD PLoS One.
It has been demonstrated that SIgA has the capacity to opsonize particles and microorganisms, enhancing phagocytic and microbicide activities through increased superoxide anion production by the phagocytes in the colostrum. Breast milk T cells differ both in relative abundance and quality when compared to the T cells found in peripheral blood. J Immunol. Activated and memory T lymphocytes in human milk. Human milk-derived B cells: a highly activated switched memory cell population primed to secrete antibodies.
This is an important finding given that intramammary breast milk has traditionally been considered sterile. Sharing of bacterial strains between breast milk and infant feces. J Hum Lact. The human milk microbiota: origin and potential roles in health and disease. Pharmacol Res. Human milk probiotic Lactobacillus fermentum CECT reduces the incidence of gastrointestinal and upper respiratory tract infections in infants.
Several epidemiological and experimental studies have been conducted to investigate the effect of human milk against different organisms involved in respiratory and gastrointestinal infections.
These studies have demonstrated that human milk has antibodies against Shigella, Salmonella typhimurium, Campylobacter, Vibrio cholerae, Haemophilus influenzae, Streptococcus pneumoniae, Bordetella pertussis , respiratory syncytial virus, HIV, and other pathogens. Passive acquisition of protective antibodies reactive with Bordetella pertussis in newborns via placental transfer and breast-feeding.
Increasing breast-feeding rates to reduce infant illness at the community level. Breast-feeding protects against celiac disease. Association between breast-feeding and asthma in 6-year-old children: findings of a prospective birth cohort study. Maternal asthma, infant feeding, and the risk of asthma in childhood. J Allergy Clin Immunol. Long-term relation between breast-feeding and development of atopy and asthma in children and young adults: a longitudinal study.
It is known that the risk of death from diarrhea can be reduced from 14 to 24 times in infants fed human milk, and that the frequency of diarrhea increases as the milk is replaced by other sources, until full weaning.
A warm chain for breast-feeding. This effect is illustrated in a study conducted in Brazil showing that exclusive breastfeeding reduces the risk of death from diarrhea by Evidence for protection by breast-feeding against infant deaths from infectious diseases in Brazil.
SIgA antibodies present in the colostrum and milk of Brazilian women have an important role in protecting against infections by enteropathogenic E. Breast-feeding protection against enteropathogenic Escherichia coli. Rev Microbiol. Next, it was demonstrated that SIgA was the primary mediator of bacterial inhibition, and that these antibodies alone, which are reactive with intimin, the main adhesin in EPEC, responsible for the binding of the bacteria to enterocytes, were able to strongly inhibit the adhesion of EPEC to the HEp-2 cells mentioned above.
In turn, all samples of colostrum and milk from the mothers studied presented antibodies for intimin and other virulence factors of EPEC. Identification of immunodominant region within the C-terminal cell binding domain of intimin alpha and beta from enteropathogenic Escherichia coli. Human colostrum and serum contain antibodies reactive to the intimin-binding region of the enteropathogenic Escherichia coli.
Similar data were found in samples of mothers of term newborns with low birth weight and premature babies. Inhibition of enteropathogenic Escherichia coli to HEp-2 cells by colostrum and milk from mothers delivering low-birth-weight neonates.
Eur J Pediatr. As a result of the concern for low birth weight newborns or premature infants, who often require banks of breast milk, the possibility of changing the biological properties of colostrum and milk was investigated after being subjected to the usual treatments of pasteurization, lyophilization, and exposure to microwaves. Effects of microwave radiation on anti-infective factors in human milk. These treatments did not alter the ability to inhibit bacterial adhesion, although pasteurization partially reduced the total IgA level and the level of anti-EPEC antibodies.
Effect of microwave radiation, pasteurization and lyophilization on the ability of human milk to inhibit Escherichia coli adherence to HEp-2 cells.
In a study conducted with a sample of colostrum from one parturient woman with IgA deficiency, inhibitory activity was observed both for adhesion of EPEC and invasion of enteroinvasive E. Furthermore, a high level of SIgM has been described in this secretion, which could represent a compensatory phenomenon to the SIgA deficiency.
Study of colostrum of a patient with Selective IgA deficiency. Allergol Immunopathol Madr. The inhibitory activity on the adhesion of shiga-like toxin-producing E. Colostrum from healthy Brazilian women inhibits adhesion and contains IgA antibodies reactive with Shiga toxin-producing Escherichia coli. Inhibition of enteroaggregative Escherichia coli adhesion to HEp-2 cells by secretory immunoglobulin A from human colostrum.
Pediatr Infect Dis J. Human colostrum contains IgA antibodies reactive to colonization factors I and II of enterotoxigenic Escherichia coli.
Int Arch Allergy Immunol. Which should I choose? Authors Topics. Home Blogs Topics Intermountain Moms Facebook Twitter. Kasee Bailey Apr 20,
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